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Pathophysiology Neonatal Jaundice

Neonatal physiologic jaundice results from simultaneous occurrence of the following 2 phenomena:

Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates.

Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin water soluble (conjugation).

Physiologic Mechanisms of Neonatal Jaundice

Increased Bilirubin Load on Liver Cell

Increased erythrocyte volume

Decreased erythrocyte survival

Increased early-labeled bilirubin*

Increased enterohepatic circulation of bilirubin

Decreased Hepatic Uptake of Bilirubin From Plasma

Decreased ligandin

Decreased Bilirubin Conjugation

Decreased uridine diphosphoglucuronosyl transferase activity

Defective Bilirubin Excretion

Excretion impaired but not rate limiting

* Early-labeled bilirubin refers to the bilirubin that does not come from the turnover of effete red blood cells. This bilirubin is derived from ineffective erythropoiesis and the turnover of nonhemoglobin heme, primarily in the liver.

The TSB concentration reflects a combination of the effectsof bilirubin production, conjugation, and enterohepatic circulation.The factors that affect these processes account for the bilirubinemiathat occurs in virtually all newborns.

Physiological jaundice

Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This common condition is called physiological jaundice. This pattern of hyperbilirubinemia has been classified into two functionally distinct periods.

Phase one

Term infants – jaundice lasts for about 5 days with a rapid rise of serum bilirubin up to 12 mg/dL.

Preterm infants: For preterm infants jaundice lasts for about a week, with a rapid rise of serum bilirubin up to 15 mg/dL.

In babies who receive exclusive breast feedings, phase two can last more than 1 month.

Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism and is formed through oxidation-reduction reactions. Approximately 75% of bilirubin is derived from hemoglobin, but degradation of myoglobin, cytochromes, and catalase also contributes. In the first oxidation step, biliverdin is formed from heme through the action of heme oxygenase, the rate-limiting step in the process, releasing iron and carbon monoxide. The iron is conserved for reuse, whereas carbon monoxide is excreted through the lungs and can be measured in the patient’s breath to quantify bilirubin production.

Next, water-soluble biliverdin is reduced to bilirubin, which, because of the intramolecular hydrogen bonds, is almost insoluble in water in its most common isomeric form (bilirubin IX α Z,Z). Because of its hydrophobic nature, unconjugated bilirubin is transported in the plasma tightly bound to albumin. Binding to other proteins and erythrocytes also occurs, but the physiologic role is probably limited. Binding of bilirubin to albumin increases postnatally with age and is reduced in infants who are ill.

The presence of endogenous and exogenous binding competitors, such as certain drugs, also decreases the binding affinity of albumin for bilirubin. A minute fraction of unconjugated bilirubin in serum is not bound to albumin. This free bilirubin is able to cross lipid-containing membranes, including the blood-brain barrier, leading to neurotoxicity. In fetal life, free bilirubin crosses the placenta, apparently by passive diffusion, and excretion of bilirubin from the fetus occurs primarily through the maternal organism.

In the liver, albumin is bound to a receptor on the cell surface when the bilirubin-albumin complex reaches the hepatocyte, and bilirubin is transported into the cell, where it binds to ligandin. Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin concentrations are low at birth but rapidly increase over the first few weeks of life. Ligandin concentrations may be increased by the administration of pharmacologic agents such as phenobarbital.

Bilirubin is bound to glucuronic acid (conjugated) in the hepatocyte endoplasmic reticulum in a reaction catalyzed by uridine diphosphoglucuronyltransferase (UDPGT). Monoconjugates are formed first and predominate in the newborn. Diconjugates appear to be formed at the cell membrane and may require the presence of the UDPGT tetramer.

Bilirubin conjugation is biologically critical because it transforms a water-insoluble bilirubin molecule into a water-soluble molecule. Water-solubility allows conjugated bilirubin to be excreted into bile. UDPGT activity is low at birth but increases to adult values by age 4-8 weeks. In addition, certain drugs (phenobarbital, dexamethasone, clofibrate) can be administered to increase UDPGT activity.

Infants who have Gilbert syndrome or who are compound heterozygotes for the Gilbert promoter and structural mutations of the UDPGT1A1 coding region are at an increased risk of significant hyperbilirubinemia. Interactions between the Gilbert genotype and hemolytic anemias such as glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency, hereditary spherocytosis, or ABO hemolytic disease also appear to increase the risk of severe neonatal jaundice.

Further, the observation of jaundice in some infants with hypertrophic pyloric stenosis may also be related to a Gilbert-type variant. Genetic polymorphism for the organic anion transporter protein OATP-2 correlates with a 3-fold increased risk for developing marked neonatal jaundice. Combination of the OATP-2 gene polymorphism with a variant UDPGT1A1 gene further increases this risk to 22-fold. Studies also suggest that polymorphisms in the gene for glutathione-S-transferase (ligandin) may contribute to higher levels of total serum bilirubin.

Thus, some interindividual variations in the course and severity of neonatal jaundice may be explained genetically. As the impact of these genetic variants is more fully understood, development of a genetic test panel for risk of severe or prolonged neonatal jaundice may become feasible.

Once excreted into bile and transferred to the intestines, bilirubin is eventually reduced to colorless tetrapyrroles by microbes in the colon. However, some deconjugation occurs in the proximal small intestine through the action of B-glucuronidases located in the brush border. This unconjugated bilirubin can be reabsorbed into the circulation, increasing the total plasma bilirubin pool. This cycle of uptake, conjugation, excretion, deconjugation, and reabsorption is termed the enterohepatic circulation. The process may be extensive in the neonate, partly because nutrient intake is limited in the first days of life, prolonging the intestinal transit time.

In mother-infant dyads who are experiencing difficulties with the establishment of breast feeding, inadequate fluid and nutrient intake often leads to significant postnatal weight loss in the infant. Such infants have an increased risk of developing jaundice through increased enterohepatic circulation, as described above. This phenomenon is often referred to as breastfeeding jaundice and is different from the breast milk jaundice described below.

Certain factors present in the breast milk of some mothers may also contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice). β -glucuronidase may play a role by uncoupling bilirubin from its binding to glucuronic acid, thus making it available for reabsorption. Data suggest that the risk of breast milk jaundice is significantly increased in infants who have genetic polymorphisms in the coding sequences of the UDPGT1A1 or OATP2 genes. Although the mechanism that causes this phenomenon is not yet agreed on, evidence suggests that supplementation with certain breast milk substitutes may reduce the degree of breast milk jaundice (see Other therapies).

Neonatal jaundice, although a normal transitional phenomenon in most infants, can occasionally become more pronounced. Blood group incompatibilities (eg, Rh, ABO) may increase bilirubin production through increased hemolysis. Historically, Rh isoimmunization was an important cause of severe jaundice, often resulting in the development of kernicterus. Although this condition has become relatively rare in industrialized countries following the use of Rh prophylaxis in Rh-negative women, Rh isoimmunization remains common in developing countries.

Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased jaundice, and increased hemolysis appears to have been present in some of the infants reported to have developed kernicterus in the United States in the past 10-15 years. The possible interaction between such conditions and genetic variants of the Gilbert and UDPGT1A1 genes, as well as genetic variants of several other proteins and enzymes involved in bilirubin metabolism, is discussed above.